19.3 Organ Transplantation and Rejection

Organ Transplantation and Immune Responses

Organ transplantation saves lives, but the recipient's immune system often recognizes the transplanted tissue as foreign and attacks it. Understanding how the immune system distinguishes "self" from "non-self" is central to grasping why rejection happens and how clinicians work to prevent it.

Role of HLAs in Transplantation

Human leukocyte antigens (HLAs) are cell surface proteins encoded by the major histocompatibility complex (MHC) genes. Their normal job is to present antigenic peptides to T cells, which is how the immune system identifies threats. MHC class I molecules present peptides to CD8+ cytotoxic T cells, while MHC class II molecules present peptides to CD4+ helper T cells.

In transplantation, HLAs become the main factor in compatibility. The closer the HLA match between donor and recipient, the lower the chance of graft rejection. When HLAs don't match, the recipient's T cells recognize the donor tissue as foreign and mount an immune response against it.

Before transplantation, two key steps help assess compatibility:

1. HLA typing identifies the specific HLA alleles of both donor and recipient using serological or molecular methods.
2. Cross-matching checks whether the recipient already has preformed antibodies against the donor's HLAs. If they do, rejection can be immediate and severe.

Even with good HLA matching, most transplant recipients need immunosuppressive drugs to prevent rejection. Common classes include:

• Calcineurin inhibitors (tacrolimus, cyclosporine) that block T cell activation
• Corticosteroids (prednisone) that broadly dampen inflammation
• Anti-proliferative agents (mycophenolate mofetil) that inhibit lymphocyte division

Types of Tissue Grafts

Not all transplants carry the same risk of rejection. The type of graft determines how strongly the immune system will react.

• Autograft: Tissue moved from one site to another on the same person. No immune response occurs because the tissue is self. A common example is using a patient's own skin to cover a burn wound.
• Isograft: Tissue transplanted between genetically identical individuals, such as monozygotic (identical) twins. Because they share the same HLA alleles, no immune rejection occurs. These are rare simply because most people don't have an identical twin available as a donor.
• Allograft (homograft): Tissue transplanted between genetically different individuals of the same species. This is the most common transplant scenario (kidney, heart, liver, bone marrow). Because donor and recipient HLAs differ, allografts can trigger an immune response, and immunosuppression is typically required.
• Xenograft (heterograft): Tissue transplanted between different species. These provoke the strongest immune response due to large genetic differences. Clinical use is limited, though some processed animal tissues are used, such as porcine heart valves and bovine pericardial patches, where the tissue is treated to reduce immunogenicity.

Causes and Consequences of GVHD

Graft-versus-host disease (GVHD) is a unique complication that flips the usual rejection scenario. Instead of the recipient's immune system attacking the graft, donor immune cells attack the recipient's body. This happens most often after allogeneic hematopoietic stem cell transplantation (HSCT), because the graft contains immunocompetent donor T cells. HLA mismatches between donor and recipient increase the risk.

GVHD comes in two forms:

• Acute GVHD typically develops within the first 100 days post-transplant. It primarily targets three organ systems: the skin (rash), the liver (jaundice from bile duct damage), and the gastrointestinal tract (diarrhea, abdominal pain).
• Chronic GVHD develops after 100 days and can affect multiple organs. It often resembles autoimmune disorders, causing skin thickening and discoloration, dry mouth and eyes, and lung dysfunction.

Prevention and treatment rely on immunosuppressive therapy, including prophylactic immunosuppression before symptoms appear, and corticosteroids or calcineurin inhibitors if GVHD develops.

There is, however, a beneficial side to this process. In patients who received HSCT for blood cancers like leukemias or lymphomas, donor T cells can also recognize and destroy residual tumor cells. This graft-versus-tumor (GVT) effect helps prevent disease relapse after transplant. Clinicians sometimes try to balance just enough immune activity to preserve the GVT effect while controlling GVHD.

Transplant Rejection and Tolerance

Rejection occurs when the recipient's immune system identifies the transplanted organ as foreign and attacks it. This can happen at different time points:

• Hyperacute rejection occurs within minutes to hours, caused by preformed antibodies against donor antigens. Cross-matching before surgery is designed to prevent this.
• Acute rejection develops over days to months and is primarily T cell-mediated. This is the most common type and is usually treatable with increased immunosuppression.
• Chronic rejection develops over months to years and involves both immune and non-immune mechanisms. It leads to gradual loss of organ function and is the leading cause of long-term graft failure.

Immunosuppression prevents rejection but comes with trade-offs. A suppressed immune system means increased susceptibility to opportunistic infections and a higher risk of certain cancers, particularly lymphomas and skin cancers.

The ideal outcome is tolerance, where the recipient's immune system accepts the transplanted organ without ongoing immunosuppression. True tolerance is rare in clinical practice, but it remains an active area of research. Histocompatibility, the degree of HLA similarity between donor and recipient, is the single biggest factor influencing whether transplantation succeeds long-term.